Fezolinetant preparation procedure

Abstract

Fezolinetant preparation procedure. The present invention relates to a process for obtaining fezolinetant that allows for the production of said product with high purity and enantiomeric excess through the use of trifluoromethanesulfonic acid. The present invention also relates to the trifluoromethanesulfonic acid salt of fezolinetant and to the use of said salt in the production of fezolinetant.

Description

Fezolinetant preparation procedure Field of invention The present invention relates to a process for obtaining fezolinetant. The present invention also relates to the trifluoromethanesulfonic acid salt of fezolinetant, to the compound ((5R)-4-(4-fluorobenzoyl)-5-methyl-3,5-dihydro-2H-pyrazin-6-yl)trifluoromethanesulfonate, and to the use of these compounds in obtaining fezolinetant. Background of the invention Fezolinetant is a selective, non-hormonal antagonist of the neurokinin 3 (NK3) receptor. It blocks the binding of neurokinin B (NKB) to the kisspeptin / neurokinin B / dynorphin (KNDy) neuron, which is postulated to restore the balance of KNDy neuronal activity in the thermoregulatory center of the hypothalamus. Fezolinetant is approved for use in the treatment of moderate to severe vasomotor symptoms (VMS), or hot flashes, associated with menopause. Fezolientant, also known by its IUPAC name (4-fluorophenyl)-[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]methanone or as (R)-(4-fluorophenyl)-(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-(8H)-yl)methanone, has the chemical structure shown below . Document WO 2014 / 154895 A1 describes in general terms the production of compounds of the fezolinetant family according to the synthetic route shown below: The above procedure applied to obtaining fezolinetant could be exemplified by the following scheme, which coincides with the procedure described by Hoveyda et al. [ACS Med Chem Lett., 2015, 6, 736-740]: WO 2016 / 046398 A1 discloses another procedure for obtaining fezolinetant via a modified chiral synthetic route. As described therein, the prior art synthesis of fezolinetant (in particular, reference is made to WO 2011 / 121137 A1), which involves first reacting (R)-3-methylpiperazin-2-one protected with a tert-butoxycarbonyl group with Et3OBF4, followed by reaction with a carbohydrazide derivative and cyclization, represents reaction steps particularly susceptible to racemization. Therefore, obtaining intermediates and products with high chiral purity is feasible but not reproducible. The solution proposed in WO2016 / 046398A1 is the synthetic route shown below: US patent 2021 / 0094955 A1 discloses the production of fezolinetant salts with certain acids and their use as active ingredients in pharmaceutical compositions for the prevention and / or treatment of NK3 receptor-related diseases. However, it does not mention that the salts obtained can be used to increase the chemical or chiral purity of the fezolinetant compound. In view of the above, there is a need to provide new procedures for obtaining fezolinetant that yield the product with high chemical and / or enantiomeric purity, particularly higher than those of the procedures described in the state of the art. Summary of the invention The inventors have discovered a new process for obtaining fezolinetant that yields the product with high purity and enantiomeric excess. This process involves the reaction of (R)-3-methylpiperazin-2-one, with the optionally protected amino group, with trifluoromethanesulfonic acid anhydride to yield a new intermediate in the synthesis of fezolinetant, which is the compound ((5R)-4-(4-fluorobenzoyl)-5-methyl-3,5-dihydro-2H-pyrazin-6-yl)trifluoromethanesulfonate. Furthermore, in this process, after obtaining fezolinetant, this compound is transformed into the corresponding trifluoromethanesulfonic acid salt of fezolinetant and then converted back into fezolinetant. The inventors have found that this set of reaction steps yields fezolinetant with high purity and enantiomeric excess, as shown in the examples. Therefore, in a first aspect, the present invention relates to a process for preparing fezolinetant comprising: a) react a compound of formula (I) with a compound of formula (II) to obtain a compound of formula (III) wherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph ​​and tert-butoxyl, and X is: i) Cl when R is 4-fluorophenyl or -OCH2Ph, or ii) -OC (=O) -O-tert-butyl when R is tert-butoxyl; b) reacting the compound of formula (III) with trifluoromethanesulfonic acid anhydride, adding 3-methyl-1,2,4-thiadiazol-5-carbohydrazide and subjecting the resulting mixture to heating at a temperature of at least 40 °C in the presence of an alcohol solvent to obtain a compound of formula (IV) wherein R is selected from the group consisting of 4-fluorobenzoyl, -C(=O)-OCH2Ph ​​and H; When R is 4-fluorobenzoyl in the compound of formula (IV) obtained in step b), the procedure is continued with step e), dispensing with steps c) and d); c) when R is -C (=O) -OCH2Ph ​​in the compound of formula (IV) obtained in step b), reacting said compound of formula (IV) with a source of hydrogen to obtain a compound of formula (IV) in which R is H and reacting said compound of formula (IV) in which R is H with 4-fluorobenzoyl chloride to obtain a compound of formula (IV) in which R is 4-fluorobenzoyl; d) when R is H in the compound of formula (IV) obtained in step b), react said compound of formula (IV) with 4-fluorobenzoyl chloride to obtain a compound of formula (IV) wherein R is 4-fluorobenzoyl; e) reacting the compound of formula (IV) in which R is 4-fluorobenzoyl obtained in steps b), c) or d) with trifluoromethanesulfonic acid to obtain the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) and f) treating the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) with a basic medium to obtain fezolinetant of formula (IVa) In a second aspect, the invention relates to the trifluoromethanesulfonic acid salt of fezolinetant of formula In a third aspect, the invention relates to a compound of formula (VI) wherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph ​​and tert-butoxyl. In a fourth aspect, the invention relates to the use of the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) as defined in the second aspect or of the compound of formula (VI) as defined in the third aspect in a process for preparing fezolinetant of formula (IVa) Description of the figures Figure 1 shows the powder X-ray diffractogram of the trifluoromethanesulfonic acid salt of fezolinetant. Figure 2 shows the X-ray diffractogram of fezolinetant powder. Detailed description of the invention In one aspect, the present invention relates to a process for preparing fezolinetant comprising: a) react a compound of formula (I) with a compound of formula (II) to obtain a compound of formula (III) wherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph ​​and tert-butoxyl, and X is: i) Cl when R is 4-fluorophenyl or -OCH2Ph, or ii) -OC (=O) -O-tert-butyl when R is tert-butoxyl; b) react the compound of formula (III) with trifluoromethanesulfonic acid anhydride, add 3-methyl-1,2,4-thiadiazol-5-carbohydrazide and subject the resulting mixture to heating at a temperature of at least 40 °C in the presence of an alcohol solvent to obtain a compound of formula (IV) wherein R is selected from the group consisting of 4-fluorobenzoyl, -C(=O)-OCH2Ph ​​and H; When R is 4-fluorobenzoyl in the compound of formula (IV) obtained in step b), the procedure is continued with step e), dispensing with steps c) and d); c) when R is -C(=O)-OCH2Ph ​​in the compound of formula (IV) obtained in step b), c1) reacting said compound of formula (IV) with a source of hydrogen to obtain a compound of formula (IV) in which R is H and c2) reacting said compound of formula (IV) in which R is H with 4-fluorobenzoyl chloride to obtain a compound of formula (IV) wherein R is 4-fluorobenzoyl; d) when R is H in the compound of formula (IV) obtained in step b), react said compound of formula (IV) with 4-fluorobenzoyl chloride to obtain a compound of formula (IV) wherein R is 4-fluorobenzoyl; e) reacting the compound of formula (IV) in which R is 4-fluorobenzoyl obtained in steps b), c) or d) with trifluoromethanesulfonic acid to obtain the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) and f) treating the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) with a basic medium to obtain fezolinetant of formula (IVa) The first step of the procedure, step a) is to react a compound of formula (I) with a compound of formula (II) to obtain a compound of formula (III) wherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph ​​and tert-butoxyl, and X is: i) Cl when R is 4-fluorophenyl or -OCH2Ph, or ii) -OC (=O) -O-tert-butyl when R is tert-butoxyl. The compound of formula (I) is (R)-3-methylpiperazin-2-one. In one embodiment, in step a) of the process, R is 4-fluorophenyl and X is Cl in the compound of formula (II). Therefore, in this embodiment, step a) of the process is to react (R)-3-methylpiperazin-2-one of formula (I) with 4-fluorobenzoyl chloride (IIa) (compound of formula (II) wherein R is 4-fluorophenyl and X is Cl) to give (R)-4-(4-fluorobenzoyl)-3-methylpiperazin-2-one (IIIa), i.e., a compound of formula (III) wherein R is 4-fluorophenyl. Preferably, the molar ratio of R)-3-methylpiperazin-2-one of formula (I) to 4-fluorobenzoyl chloride (compound of formula (II) wherein R is 4-fluorophenyl and X is Cl) is 1:1 to 1:1, 5, more preferably 1:1 to 1:1, 2, even more preferably 1:1 to 1:1, 1. In another embodiment, in step a) of the procedure, R is -OCH2Ph ​​and X is Cl in the compound of formula (II). Therefore, in this embodiment, step a) of the procedure is to react (R)-3-methylpiperazin-2-one of formula (I) with benzyl chloroformate (IIb) (compound of formula (II) in which R is -OCH2Ph ​​and X is Cl) to give (R)-2-methyl-3-oxopiperazine-1-carboxylate (IIIb), i.e., a compound of formula (III) in which R is -OCH2Ph. Preferably, the molar ratio of R)-3-methylpiperazin-2-one of formula (I) to benzyl chloroformate (compound of formula (II) wherein R is -OCH2Ph ​​and X is Cl) is 1:1 to 1:1, 5, more preferably 1:1 to 1:1, 3, even more preferably 1:1 to 1:1, 2. In another embodiment, in step a) of the procedure, R is tert-butoxyl and X is -OC(=O)-O-tert-butyl in the compound of formula (II). Therefore, in this embodiment, step a) of the procedure is to react (R)-3-methylpiperazin-2-one of formula (I) with di-tert-butyl dicarbonate (IIc) (compound of formula (II) in which R is tert-butoxyl and X is -OC(=O)-O-tert-butyl) to give (R)-2-methyl-3-oxopiperazine-1-carboxylate tert-butyl (IIIc), i.e., a compound of formula (III) in which R is tert-butoxyl. Preferably, the molar ratio of R)-3-methylpiperazin-2-one of formula (I) to di-tert-butyl dicarbonate (IIc) (compound of formula (II) wherein R is tert-butoxyl and X is -OC (=O)-O-tert-butyl) is 1:1 to 1:1, 5, more preferably 1:1 to 1:1, 3, even more preferably 1:1 to 1:1, 2. Preferably, the compound of formula (II) is 4-fluorobenzoyl chloride (IIa) (compound of formula (II) wherein R is 4-fluorophenyl and X is Cl), and the compound of formula (III) is (R)-4-(4-fluorobenzoyl)-3-methylpiperazin-2-one (IIIa) (compound of formula (III) wherein R is 4-fluorophenyl). Preferably, step a) is performed in the presence of a base. The term "base" refers to an organic or inorganic compound, a substance capable of accepting a proton (from an acid). Preferably, the base used in step a) is a tertiary amine; more preferably the base is selected from the group consisting of N-methylmorpholine, triethylamine and a mixture thereof. In a more preferred embodiment, the molar ratio of (R)-3-methylpiperazin-2-one of formula (I) to base in step a) is 1:1 to 1:1, 5, more preferably 1:1 to 1:1, 3, even more preferably 1:1 to 1:1, 2. Preferably, step a) is carried out in the presence of a polar aprotic organic solvent. The term "polar aprotic organic solvent" refers to a liquid compound that lacks acidic protons (such as hydroxyl groups) and is polar, that is, it has a dielectric constant of at least 5. Examples of polar aprotic organic solvents are dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, among others. Preferably, the polar aprotic organic solvent of step a) is selected from the group consisting of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran and mixtures thereof, most preferably dichloromethane. Preferably, step a) is performed at a temperature of -5 to 25 ºC. The compound of formula (III) obtained in step a) can be isolated from the reaction medium by conventional procedures of the technique, such as extraction, washing, solvent removal, filtration, crystallization and combination thereof. In one particular embodiment, the compound of formula (III) is crystallized in a mixture of ethyl acetate and tert-butyl methyl ether. The next step in the procedure, step b), is to react the compound of formula (III) with trifluoromethanesulfonic acid anhydride, add 3-methyl-1,2,4-thiadiazol-5-carbohydrazide and subject the resulting mixture to heating at a temperature of at least 40 °C in the presence of an alcohol solvent to obtain a compound of formula (IV) wherein R is selected from the group consisting of 4-fluorobenzoyl, -C(=O)-OCH2Ph ​​and H. The compound of formula (III) is the one described above for step a). Therefore, in the compound of formula (III) R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph ​​and tert-butoxyl, preferably 4-fluorophenyl. In the compound of formula (IV) R is selected from the group consisting of 4-fluorobenzoyl, -C (=O) -OCH2Ph ​​and H, preferably 4-fluorobenzoyl. When R is 4-fluorophenyl in the compound of formula (III) , R is 4-fluorobenzoyl in the compound of formula (IV) , a compound that corresponds to the fezolinetant of formula (IVa) . Therefore, in one embodiment R is 4-fluorophenyl, X is Cl and R is 4-fluorobenzoyl. When R is -OCH2Ph ​​in the compound of formula (III) , R is -C (=O) -OCH2Ph ​​in the compound of formula (IV) , which corresponds to the structure of the compound of formula (IVb) . Therefore, in another embodiment R is -OCH2Ph, X is Cl and R is -C (=O) -OCH2Ph. When R is tert-butoxyl in the compound of formula (III) , R is H in the compound of formula (IV) , which corresponds to the structure of the compound of formula (IVc) . Therefore, in another embodiment R is tert-butoxyl, X is -OC (=O) -O-tert-butyl and R is H. The reaction of the compound of formula (III) with trifluoromethanesulfonic acid anhydride from step b) yields a new intermediate in the synthesis of fezolinetant, which is the compound of formula (VI) wherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph ​​and tert-butoxyl. In particular, the reaction of the compound of formula (III) in which R is 4-fluorophenyl with trifluoromethanesulfonic acid anhydride of step b yields a new intermediate in the synthesis of fezolinetant which is the compound of formula (VIa) Preferably, the reaction of the compound of formula (III) with trifluoromethanesulfonic acid anhydride of step b) is carried out in the presence of a polar aprotic organic solvent, as defined above, more preferably dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran or a mixture thereof, even more preferably dichloromethane. Preferably, in step b), the reaction of the compound of formula (III) with trifluoromethanesulfonic acid anhydride is carried out in the presence of a base. The term base is as defined above. Preferably, the base is a tertiary amine, more preferably the base is selected from the group consisting of triethylamine, diisopropylethylamine and mixtures thereof, most preferably triethylamine. Preferably, the reaction of the compound of formula (III) with trifluoromethanesulfonic acid anhydride of step b) is carried out at a temperature of -25 to -10 °C. In a preferred embodiment, the molar ratio of the compound of formula (III) to the trifluoromethanesulfonic acid anhydride of step b) is 1:1 to 1:2, preferably 1:1.3 to 1:1.7, more preferably 1:1.5 to 1:1.6. In step b), after the reaction of the compound of formula (III) with trifluoromethanesulfonic acid anhydride, the addition of 3-methyl-1,2,4-thiadiazol-5-carbohydrazide is carried out and the mixture is heated to a temperature of at least 40°C in the presence of an alcohol solvent. Preferably, the heating of step b) is to a temperature of at least 50°C, more preferably 60 to 110°C, more preferably 65 to 100°C, more preferably 70 to 90°C, even more preferably 75 to 85°C. The "solvent alcohol" of step b) refers to an alkanol, i.e., a linear or branched alkyl group attached to a hydroxyl group, preferably having 1 to 6 carbon atoms, preferably 2 to 4 carbon atoms, more preferably 2 or 3 carbon atoms, and most preferably 3 carbon atoms. Examples of alkanols are methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tert-butanol. In a preferred embodiment, the solvent alcohol of step b) is selected from the group consisting of isopropanol, n-propanol, ethanol, and mixtures thereof, most preferably isopropanol. In a preferred embodiment, the molar ratio of the compound of formula (III) to the 3-methyl-1,2,4-thiadiazol-5-carbohydrazide of step b) is 1:1 to 1:1,5, preferably 1:1 to 1:1,3, more preferably 1:1,1 to 1:1,25. Preferably, the compound of formula (IV) obtained in step b) is not isolated from the reaction medium, and the procedure proceeds directly to the next step, particularly when the next step is step e), i.e., when the compound of formula (IV) R is 4-fluorobenzoyl, meaning the compound is fezolinetant of formula (IVa). If it is desired to isolate the compound of formula (IV) from the reaction medium, this can be done using conventional techniques such as extraction, washing, solvent removal, filtration, crystallization, and combinations thereof. The following steps of the procedure are steps c), d), e), and f). Depending on the nature of group R in the compound of formula (IV) obtained in step b), either step c), step d), or neither of steps c) and d) will be carried out. Step e) will be carried out directly (when R is 4-fluorobenzoyl in the compound of formula (IV) obtained in step b), i.e., when fezolinetant of formula (IVa) is obtained in step b). Steps d) and e) will be carried out (when R is H in the compound of formula (IV) obtained in step b), i.e., when the compound of formula (IVc) is obtained in step b). Steps c) and e) will be carried out when R is -C(=O)-OCH2Ph ​​in the compound of formula (IV) obtained in step b), i.e., when the compound of formula (IVb) is obtained in step b). After step e), step f) will be carried out in all cases. Step c) is only performed when R is -C (=O) -OCH2Ph ​​in the compound of formula (IV) obtained in step b), that is, when in step b) the compound of formula (IVb) has been obtained. Step c) comprises substeps c1) and c2). In step c1) said compound of formula (IV) in which R is -C (=O) -OCH2Ph ​​(i.e., the compound of formula (IVb) ) is reacted with a source of hydrogen to obtain a compound of formula (IV) in which R is H (i.e., the compound of formula (IVc) ). This reaction is widely known to experts in the field, as it involves the deprotection of a carboxybenzyl group. The term "hydrogen source" refers to H2 or any substance capable of generating H2 in the reaction medium, such as hydrazine, cyclohexene, or dihydronaphthalene, preferably H2. Preferably, H2 is used as the hydrogen source for step c1). Furthermore, the reaction is preferably carried out in the presence of a palladium-based catalyst, such as palladium on carbon. Preferably, step c1) is carried out in the presence of an alcohol solvent, as defined above, preferably an alcohol containing 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 carbon atom. Preferably, step c1) is performed at a temperature of 20 to 25 ºC. After completing step c1), the product with the unprotected amino group, i.e., a compound of formula (IV) in which R is H (i.e., the compound of formula (IVc)), can be isolated from the reaction medium by conventional procedures of the technique, such as extraction, washing, solvent removal, filtration, crystallization and combination thereof. Step c2) is then carried out to transform the compound of formula (IV) in which R is H (i.e., the compound of formula (IVc)) ​​into a compound of formula (IV) in which R is 4-fluorobenzoyl (i.e., the compound of formula (IVa) or fezolinetant). This step c2) is the same as step d) described below. The next step in the procedure is step d). This step is only performed when R is H in the compound of formula (IV) (i.e., in the compound of formula (IVc)). Therefore, it is performed when in step b) a compound of formula (IV) in which R is H (i.e., the compound of formula (IVc)) ​​has been obtained directly, and also when step c1) has been performed, which consists of going from a compound of formula (IV) in which R is -C(=O)-OCH2Ph ​​(i.e., the compound of formula (IVb)) to a compound of formula (IV) in which R is H (i.e., the compound of formula (IVc)), and thus a compound of formula (IV) in which R is H (i.e., the compound of formula (IVc)) ​​has also been obtained. In step d) and / or in step c2) said compound of formula (IV) wherein R is H (i.e., the compound of formula (IVc)) ​​is reacted with 4-fluorobenzoyl chloride to obtain a compound of formula (IV) wherein R is 4-fluorobenzoyl (i.e., the compound of formula (IVa) or fezolinetant). Preferably, step d) and / or step c2) are carried out in the presence of a base. The base is as defined above. Preferably, the base in step d) and / or step c2) is a tertiary amine, most preferably N-methylmorpholine. Preferably, step d) and / or step c2) is carried out in the presence of a polar aprotic organic solvent, as defined above, more preferably the polar aprotic organic solvent is dichloromethane. In a preferred embodiment, the molar ratio of the compound of formula (IV) wherein R is H (i.e., the compound of formula (IVc)) ​​to 4-fluorobenzoyl chloride of step d) and / or step c2) is 1:1 to 1:1, 5, preferably 1:1 to 1:1, 2, more preferably 1:1 to 1:1, 1. Preferably, step d) and / or step c2) is carried out at a temperature of 0 to 5 ºC. After completing step d) and / or step c2), the product obtained, i.e., a compound of formula (IV) in which R is 4-fluorobenzoyl (i.e., the compound of formula (IVa) or fezolinetant), can be isolated from the reaction medium by conventional procedures of the technique, such as extraction, washing, solvent removal, filtration, crystallization and combination thereof. Therefore, when in step b) a compound of formula (IV) has been obtained in which R is 4-fluorobenzoyl, i.e. the compound of formula (IVa) or fezolinetant, the synthesis procedure comprises carrying out step e) after having carried out step b), i.e., steps c) and d) are not carried out, as shown in the synthetic scheme below: Stage b) When in step b) a compound of formula (IV) has been obtained in which R is H, i.e. the compound of formula (IVc) , the synthesis procedure comprises carrying out step d) before carrying out step e) , as shown in the synthetic scheme below: Stage b) Finally, when in step b) a compound of formula (IV) has been obtained in which R is -C (=O) -OCH2Ph, i.e. the compound of formula (IVb) , the synthesis procedure comprises carrying out step c) before carrying out step e) , according to the synthetic scheme shown below: Stage b) The next step in the procedure is step (e), of reacting the compound of formula (IV) in which R is 4-fluorobenzoyl (i.e., the compound of formula (IVa) or fezolinetant) obtained in steps (b), (c) or (d) with trifluoromethanesulfonic acid to obtain the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) Preferably, step e) is carried out in the presence of an alcohol-type solvent. The alcohol-type solvent is as defined above, preferably isopropanol, n-propanol, ethanol, and mixtures thereof, most preferably isopropanol. In a preferred embodiment, the molar ratio of the compound of formula (IV) in which 4-fluorobenzoyl (i.e., the compound of formula (IVa) or fezolinetant) of step e) is to the trifluoromethanesulfonic acid of step e) is 1:1.5 to 1:2, preferably 1:1.5 to 1:1.8, more preferably 1:1.5 to 1:1.6. Preferably, step e) is carried out at a temperature above 40°C, more preferably at a temperature above 50°C, more preferably from 60 to 110°C, more preferably from 65 to 100°C, more preferably from 70 to 90°C, even more preferably from 75 to 85°C. The trifluoromethanesulfonic acid salt of fezolinetant of formula (V) obtained in step e) can be isolated from the reaction medium by conventional procedures of the art, such as extraction, washing, solvent removal, filtration, crystallization and combination thereof, preferably by filtration and washing. The trifluoromethanesulfonic acid salt of fezolinetant of formula (V) obtained in step e) is a novel salt of fezolinetant and has the advantage of achieving further purification of fezolinetant. The next step in the procedure is step f), , of treating the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) with a basic medium to obtain fezolinetant of formula (IVa) The expression "basic medium" refers to any substance or mixture of substances capable of neutralizing the trifluoromethanesulfonic acid of the trifluoromethanesulfonic acid salt of fezolinetant to give fezolinetant (free base). Preferably, the basic medium of step f) is a basic aqueous solution; more preferably, said basic aqueous solution is selected from the group consisting of aqueous sodium bicarbonate solution, aqueous potassium bicarbonate solution, aqueous sodium carbonate solution, aqueous potassium carbonate solution and mixtures thereof; even more preferably aqueous sodium bicarbonate solution. Preferably, step f) is performed at a temperature of 20 to 25 ºC. After completing step f), the fezolinetant obtained can be isolated from the reaction medium by conventional procedures of the technique, such as extraction, washing, solvent removal, filtration, crystallization and combination thereof, preferably filtration and washing. As explained above, the procedure of the invention yields two novel compounds, the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) and the compound of formula (VI). Therefore, in a second aspect, the invention relates to the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) Preferably, said trifluoromethanesulfonic acid salt of fezolinetant is in solid form, more preferably in crystalline solid form. In a particular embodiment, the trifluoromethanesulfonic acid salt of fezolinetant is characterized in that it has a powder X-ray diffractogram measured with CuK radiation comprising peaks at 8, 1°2, 8, 7°2, 11, 0°2, 13, 6°2, 17, 3°2, 18, 9°2, 19, 7°2, 22, 4°2 all of them with a margin of error of ± 0.2°2. In another embodiment, the trifluoromethanesulfonic acid salt of fezolinetant is characterized by having a powder X-ray diffractogram measured with CuK radiation essentially like that in Figure 1. X-ray diffractograms can be recorded using a powder diffraction system with a copper anode that emits CuK radiation with a wavelength of 1.54 Å, in particular, by following the method described in the examples. In another embodiment, the trifluoromethanesulfonic acid salt of fezolinetant is characterized in that it has a differential scanning calorimetry (DSC) diagram comprising an exothermic peak having a threshold temperature of approximately 236.8 °C ± 2 °C. The differential scanning calorimetry diagram can be obtained as described in the examples. The threshold temperature or "T onset" refers to the temperature resulting from extrapolating the baseline before the start of the transition and the baseline during energy absorption (tangent of the curve). It can be calculated as defined in DIN ISO 11357-1:2016 (E). In a third aspect, the invention relates to a compound of formula (VI) wherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph ​​and tert-butoxyl. In a preferred embodiment, R is 4-fluorophenyl and the compound has the formula (VIa) In a fourth aspect, the invention relates to the use of the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) as defined in the second aspect or of the compound of formula (VI) wherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph ​​and tert-butoxyl as defined in the third aspect in a process for preparing fezolinetant of formula (IVa) In the context of the present invention, the terms "approximate", "approximate" and "approximately" referring to a value refer to any value that is within the range defined by the value ±10% of said value, preferably ±5% of said value. The following are illustrative examples that reveal the features and advantages of the invention. However, they should not be interpreted as limiting the scope of the invention as defined in the claims. Examples Materials and methods Ultra-High Performance Liquid Chromatography The chemical purity of the products obtained was analyzed using Ultra-High Performance Liquid Chromatography (UHPLC) on a Waters Acquity instrument equipped with a photodiode detector, mass spectrometer, and thermostatically controlled oven for the column. An Acquity BEH C18 column (1.7 µm, 2.1 x 100 mm) and the mobile phases A (50 mM ammonium formate, pH 4.8 in water), B (acetonitrile), and C (water) were used under the following analytical conditions: Flow rate: 0.5 mL / min Column temperature: 45 ºC Wavelength: 220 nm Injection volume: 1 L Diluent: Mobile phase A / Mobile phase B (1:1) Gradient: The optical purity of the products obtained was analyzed using Ultra-High Performance Liquid Chromatography (UHPLC) on a Waters Acquity instrument equipped with a photodiode detector, mass spectrometer, and thermostatically controlled oven for the column. A Chiralpak IA column (4.6 x 250 mm x 5 µm) and mobile phases A (0.1% diethylamine in hexane) and B (ethanol) were used under the following analytical conditions: Flow rate: 1 mL / min Column temperature: 25 ºC Wavelength: 280 nm for fezolinetant and fezolinetant trifluoromethanesulfonic acid salt and 230 nm for the rest of the compounds. Injection volume: 1 L Diluent: Mobile Phase A / Mobile Phase B (75:25) Gradient: Isocratic Acquisition time: 20 minutes Differential Scanning Calorimetry (DSC) The DSC analysis was performed on a Mettler Toledo 822e instrument with STARe SW15 software, using the following parameters: heating range of 30 to 300 °C with a ramp of 10 °C / min and N2 flow of 50 ml / min. The measurement is made with a perforated closed capsule. X-ray crystallography (XRPD) XRPD analysis was performed using a BRUKER D2 PHASER X-ray powder diffractometer equipped with a copper anode. The radiation used was CuK with a wavelength of 1.54 Å. The following scanning parameters were used: 3-50 degrees, continuous scanning, rate: 5.6 degrees / minute. Nuclear Magnetic Resonance Analysis Proton nuclear magnetic resonance (1H-NMR) and 13C-NMR analyses were performed on a 400 MHz Brucker Avance III spectrometer. Chemical shifts were referenced to the DMSO-d6 signal (2.49 ppm for proton and 39.5 ppm for carbon). Example 1. Obtaining (R) -4- (4-fluorobenzoyl) -3-methylpiperazin-2-one (IIIa) 100.0 g (876.0 mmol) of (R)-3-methylpiperazin-2-one (I) was mixed with 1000 mL of dichloromethane at approximately 20 °C. The reaction mass was cooled to approximately 0 °C, and 98.2 mL (893.6 mmol) of N-methylmorpholine and subsequently 103.5 mL (876.0 mmol) of 4-fluorobenzoyl (IIa) chloride were added very slowly. The resulting reaction mixture was kept under stirring for 1 hour at a temperature between 0 and 5 °C. After maintenance was completed, 438 mL of a 1 N aqueous HCl solution were slowly added. The two resulting phases were separated, and the organic phase was washed with 418.1 mL of an 8 wt% aqueous NaHCO3 solution. The solvent was removed from the organic phase resulting from the subsequent treatment by vacuum distillation, and 195 mL of ethyl acetate was added to the resulting solid. The mixture was heated to reflux temperature and stirred for 10 minutes, yielding a perfect solution. 195 mL of tert-butyl methyl ether were then added, and a slight turbidity was observed in the reaction mixture. It was slowly cooled to between 5 and 10 °C and stirred for 2 hours at that temperature.The resulting solid was filtered, successively washed with two 100 ml fractions of tert-butyl methyl ether each, and dried in a vacuum oven at a temperature of approximately 40°C to obtain 172.17 g (83.2% yield, 99.95% purity by HPLC and 99.46% enantiomeric excess) of a corresponding white solid (R)-4-(4-fluorobenzoyl)-3-methylpiperazin-2-one (IIIa). Example 2. Obtaining the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl) methanone (trifluoromethanesulfonic acid salt of fezolinetant) 20.0 g (84.7 mmol) of (R)-4-(4-fluorobenzoyl)-3-methylpiperazin-2-one (IIIa) was mixed with 230 mL of dichloromethane at approximately 20 °C. The reaction mixture was cooled to approximately -15 °C, and 18.3 mL (131.2 mmol) of triethylamine was added, maintaining the reaction mixture under stirring for 10 minutes at the stated temperature. 22.2 mL (131.2 mmol) of trifluoromethanesulfonic acid anhydride was then added very slowly, maintaining the stated temperature, and the resulting reaction mixture was maintained under stirring for 10 minutes. Finally, 16.07 g (101.6 mmol) of 3-methyl-1,2,4-thiadiazol-5-carbohydrazide was slowly added, also at a temperature of approximately -15°C, and the resulting reaction mass was kept under stirring for 10 minutes at the stated temperature.The temperature of the reaction mass was allowed to evolve to approximately 20°C and was kept under stirring at that temperature for 1 hour. After maintenance was completed, the solvent was removed by vacuum distillation and 200 ml of isopropanol were added. The resulting reaction mass was heated to the reflux temperature and kept under stirring for 16 hours. After maintenance, the reaction stock showed an optical purity of approximately 98.5% by UHPLC for (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone. The reaction stock was cooled to approximately 50 °C, and 12.0 L (135.4 mmol) of trifluoromethanesulfonic acid was slowly added. The reaction mixture was heated to reflux temperature and held under stirring for 10 minutes at that temperature.The resulting solid was then slowly cooled to a temperature of approximately 20°C, filtered, successively washed with two 20 ml fractions of isopropanol each, and dried in a vacuum oven at a temperature of approximately 40°C to obtain 20.36 g (47.3% yield, 99.84% purity by HPLC and 99.88% enantiomeric excess) of a white solid corresponding to the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone. 1H-NMR (d6-DMSO, 400 MHz) (ppm): 12.16 (wides, 1H), 7.59 (dd, 2H), 7.35-7.29 (m, 2H), 5.73 (wides, 1H), 4.70-4.68 (d, 1H), 4, 30 (m, 1H) , 3, 65 (m, 1H) 2, 68 (s, 3H) , 1, 61 (d, 3H) . 13C-NMR (d6-DMSO, 400 MHz) (ppm) : 174.8, 174.1, 169.2, 163.3 (d), 154.6, 145.4, 132.1 (d), 130.0 (d, 2C), 121.1 (d) , 116, 1 (d, 2C), 62, 5, 45, 3 (2C), 25, 9, 19, 1. XRPD: 8, 1 º 2, 8, 7 º 2, 11, 0 º 2, 13, 6 º 2, 17, 3 º 2, 18, 9 º 2, 19, 7 º 2, 22, 4 º 2 all with a margin of error of ± 0, 2 º 2. The powder X-ray diffractogram of the compound is shown in Figure 1. The differential scanning calorimetry (DSC) spectrum of the compound comprises an endothermic peak exhibiting a threshold temperature of approximately 236.8 °C. Example 3. Obtaining (R) - (4-fluorophenyl) (8-methyl-3- (3-methyl-1,2,4-thiadiazol-5-yl) -5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7 (8H) -yl) methanone (fezolinetant) 76.43 g (150.3 mmol) of the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone obtained by the methodology described in Example 2 were mixed with 382 ml of water at a temperature of approximately 20 °C. A 10 wt% aqueous solution of NaHCO3 was added until a stable pH of approximately 8 was reached while maintaining the stated temperature, and the resulting mixture was kept under stirring for 1 hour. The resulting solid was filtered, successively washed with two 35 ml fractions of water each and dried in a vacuum oven at a temperature of approximately 45°C to obtain 52.51 g (97.5% yield, 99.97% purity by HPLC and 99.94% enantiomeric excess) of a white solid corresponding to (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone. XRPD: 9, 3 º 2, 9, 9 º 2, 12, 0 º 2, 13, 5 º 2, 14, 9 º 2, 15, 7 º 2, 16, 8 º 2, 18, 6 º 2, 19, 1 º 2, 19, 8 º 2, 20, 1 º 2, 21, 8 º 2, 22, 5 º 2, 24, 2 º 2, 25, 4 º 2, 27, 5 º 2 and 28, 9 º 2 all with a margin of error of ± 0.2 º 2. The powder X-ray diffractogram of the compound is shown in Figure 2. The differential scanning calorimetry (DSC) spectrum of the compound comprises an endothermic peak exhibiting a threshold temperature of approximately 169.1 °C. Example 4. Obtaining (R)-2-methyl-3-oxopiperazine-1-carboxylate tert-butyl (IIIc) 5 g (43.75 mmol) of (R)-3-methylpiperazin-2-one and 6.8 mL (48.25 mmol) of triethylamine were mixed with 25 mL of dichloromethane at approximately 20 °C. The resulting solution was cooled to approximately 0 °C and 11.0 g (50.25 mmol) of di-tert-butyl(IIc) dicarbonate was added. The temperature of the reaction mixture was allowed to rise to approximately 20 °C and the resulting solution was kept under stirring for 1 hour at that temperature. After maintenance, the reaction mixture was successively washed with 15 mL of a 1 N aqueous HCl solution and 15 mL of a saturated aqueous NaCl solution. The solvent was removed from the organic phase by vacuum distillation, and the resulting solid was crystallized from a mixture of 15 mL of methyl tert-butyl ether and 10 mL of ethyl acetate to obtain 8.35 g (89.0% yield, 99.01% purity by HPLC, and 99.89% enantiomeric excess) of a white solid corresponding to (R)-2-methyl-3-oxopiperazine-1-carboxylate tert-butyl (IIIc). Example 5. Obtaining (R)-2-methyl-3-oxopiperazine-1-carboxylate of benzyl (IIIb) 5 g (43.75 mmol) of (R)-3-methylpiperazin-2-one (I) and 6.8 mL (48.25 mmol) of triethylamine were mixed with 25 mL of dichloromethane at approximately 20 °C. The resulting solution was cooled to approximately 0 °C and 7.2 mL (50.44 mmol) of benzyl (IIb) chloroformate was added. The temperature of the reaction mixture was allowed to rise to approximately 20 °C and the resulting solution was kept under stirring for 1 hour at that temperature. After maintenance, the reaction mixture was successively washed with 15 mL of a 1 N aqueous HCl solution and 15 mL of a saturated aqueous NaCl solution. The solvent was removed from the organic phase by vacuum distillation, and the resulting solid was crystallized from a mixture of 25 mL of methyl tert-butyl ether and 15 mL of ethyl acetate to obtain 7.36 g (67.7% yield, 99.15% purity by HPLC, and 99.91% enantiomeric excess) of a white solid corresponding to benzyl(IIIb)(R)-2-methyl-3-oxopiperazine-1-carboxylate. Example 6. Obtaining the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (trifluoromethanesulfonic acid salt of fezolinetant) 2 g (9.34 mmol) of (R)-2-methyl-3-oxopiperazine-1-carboxylate (IIIc) obtained by the methodology described in Example 4 were mixed with 20 mL of dichloromethane at a temperature of approximately 20 °C. The reaction mass was cooled to a temperature of approximately -15 °C and 2.0 mL (14.35 mmol) of triethylamine was added, maintaining the reaction mass under stirring for 5 minutes at the indicated temperature. Very slowly, 2.4 mL (14.21 mmol) of trifluoromethanesulfonic acid anhydride was added, maintaining the indicated temperature, and the resulting reaction mass was maintained under stirring for 10 minutes. Next, 1.8 g (11.38 mmol) of 3-methyl-1,2,4-thiadiazol-5-carbohydrazide was slowly added, also at a temperature of approximately -15°C, and the resulting reaction mass was kept under stirring for 5 minutes at the stated temperature.The temperature of the reaction mass was allowed to evolve to approximately 20°C and was kept under stirring at that temperature for 1 hour. After maintenance was completed, the solvent was removed by vacuum distillation and 20 ml of isopropanol were added. The resulting reaction mass was heated to the reflux temperature and kept under stirring for 16 hours. After maintenance was completed, the solvent was removed by vacuum distillation to obtain a solid residue to which 20 mL of dichloromethane were added. The reaction mass was cooled to approximately 0 °C, and 2.1 mL (19.1 mmol) of N-methylmorpholine and then 1.1 mL (9.32 mmol) of 4-fluorobenzoyl chloride were added very slowly. The resulting reaction mixture was kept under stirring for 1 hour at a temperature between 0 and 5 °C. After maintenance was completed, 5 mL of a 1 N aqueous HCl solution were slowly added. The two resulting phases were separated, and the organic phase was washed with 5 mL of an 8 wt% aqueous NaHCO3 solution. The solvent was removed from the organic phase by vacuum distillation, 20 mL of isopropanol were added, and the reaction mixture was heated to approximately 50 °C. Then, 1.3 mL (14.7 mmol) of trifluoromethanesulfonic acid was slowly added. The reaction mixture was heated to reflux temperature and held under stirring for 10 minutes at that temperature.The resulting solid was then slowly cooled to a temperature of approximately 20°C, filtered, successively washed with two 5 ml fractions of isopropanol each, and dried in a vacuum oven at a temperature of approximately 40°C to obtain 1.92 g (40.4% yield, 99.81% purity by HPLC and 99.88% enantiomeric excess) of a white solid corresponding to the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone. The powder X-ray diffractogram (XRPD) and differential scanning calorimetry (DSC) spectrum of the obtained compound match those of the compound obtained following the experimental methodology described in Example 2. Example 7. Obtaining (R) - (4-fluorophenyl) (8-methyl-3- (3-methyl-1,2,4-thiadiazol-5-yl) -5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7 (8H) -yl) methanone (fezolinetant) 5.0 g (9.83 mmol) of the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone obtained by the methodology described in section 5.6 was mixed with 25 ml of water at a temperature of approximately 20 °C. A 10 wt% aqueous solution of NaHCO3 was added to a stable pH of approximately 8 while maintaining the stated temperature, and the resulting mixture was kept under stirring for 1 hour. The resulting solid was filtered, successively washed with two 5 ml fractions of water each, and dried in a vacuum oven at a temperature of approximately 45°C to obtain 3.41 g (96.8% yield, 99.91% purity by HPLC and 99.92% enantiomeric excess) of a white solid corresponding to (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone. The powder X-ray diffractogram (XRPD) and differential scanning calorimetry (DSC) spectrum of the obtained compound match those of the compound obtained following the experimental methodology described in Example 3. Example 8. Obtaining the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (trifluoromethanesulfonic acid salt of fezolinetant) 2 g (8.06 mmol) of (R)-2-methyl-3-oxopiperazine-1-carboxylate obtained by the methodology described in Example 5 were mixed with 20 mL of dichloromethane at a temperature of approximately 20 °C. The reaction mass was cooled to a temperature of approximately -15 °C and 1.7 mL (12.20 mmol) of triethylamine was added, maintaining the reaction mass under stirring for 5 minutes at the indicated temperature. Very slowly, 2.0 mL (12.12 mmol) of trifluoromethanesulfonic acid anhydride was added, maintaining the indicated temperature, and the resulting reaction mass was maintained under stirring for 10 minutes. Next, 1.53 g (9.67 mmol) of 3-methyl-1,2,4-thiadiazol-5-carbohydrazide was slowly added, also at a temperature of approximately -15°C, and the resulting reaction mass was kept under stirring for 5 minutes at the stated temperature.The temperature of the reaction mass was allowed to evolve to approximately 20°C and was kept under stirring at that temperature for 1 hour. After maintenance was completed, the solvent was removed by vacuum distillation and 20 ml of isopropanol were added. The resulting reaction mass was heated to the reflux temperature and kept under stirring for 18 hours. After maintenance, the reaction mass was cooled to approximately 20 °C and triethylamine was slowly added until the pH reached between 7 and 8. The solvent was removed from the reaction mixture by vacuum distillation, and the resulting residue was dissolved in 10 mL of ethyl acetate and 10 mL of water. The organic phase thus obtained was separated, and the solvent was removed by vacuum distillation. The resulting solid was mixed with 20 mL of methanol, and 0.10 g of 5% Pd / C was added. Two successive inerting sequences were performed using vacuum and N₂, and finally, the internal pressure of the flask was adjusted to approximately 5 bar with an atmosphere of H₂. The resulting mixture was maintained at a temperature between 20 and 25 °C and approximately 5 bar of H₂ pressure under stirring for 18 hours. After maintenance was completed, the reaction mixture was depressurized and filtered through a diatomaceous earth filter, which was then washed with two 10 mL fractions of methanol. The solvent was removed by vacuum distillation to obtain a solid residue, to which 20 mL of dichloromethane was added. The reaction mixture was cooled to approximately 0 °C, and 0.9 mL (8.19 mmol) of N-methylmorpholine was added very slowly, followed by 1.0 mL (8.46 mmol) of 4-fluorobenzoyl chloride. The resulting reaction mixture was kept under stirring for 1 hour at a temperature between 0 and 5 °C. After maintenance was completed, 5 mL of a 1 N aqueous HCl solution were slowly added. The two resulting phases were separated, and the organic phase was washed with 5 mL of an 8 wt% aqueous NaHCO3 solution. The solvent was removed from the organic phase by vacuum distillation, 20 mL of isopropanol were added, and the reaction mixture was heated to approximately 50 °C. Then, 1.1 mL (12.4 mmol) of trifluoromethanesulfonic acid was slowly added. The reaction mixture was heated to reflux temperature and held under stirring for 5 minutes at that temperature.The resulting solid was then slowly cooled to a temperature of approximately 20°C, filtered, successively washed with two 5 ml fractions of isopropanol each, and dried in a vacuum oven at a temperature of approximately 40°C to obtain 1.80 g (43.9% yield, 99.74% purity by HPLC and 99.91% enantiomeric excess) of a white solid corresponding to the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone. The powder X-ray diffractogram (XRPD) and differential scanning calorimetry (DSC) spectrum of the obtained compound match those of the compound obtained following the experimental methodology described in Example 2. Example 9. Obtaining (R) - (4-fluorophenyl) (8-methyl-3- (3-methyl-1,2,4-thiadiazol-5-yl) -5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7 (8H) -yl) methanone (fezolinetant) 5.0 g (9.83 mmol) of the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone obtained by the methodology described in Example 8 was mixed with 25 mL of water at a temperature of approximately 20 °C. A 10 wt% aqueous solution of NaHCO3 was added to a stable pH of approximately 8 while maintaining the stated temperature, and the resulting mixture was kept under stirring for 1 hour. The resulting solid was filtered, successively washed with two 5 ml fractions of water each and dried in a vacuum oven at a temperature of approximately 45°C to obtain 3.45 g (97.9% yield, 99.90% purity by HPLC and 99.92% enantiomeric excess) of a white solid corresponding to (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone. The powder X-ray diffractogram (XRPD) and differential scanning calorimetry (DSC) spectrum of the obtained compound match those of the compound obtained following the experimental methodology described in Example 3.

Claims

1. Process for preparing fezolinetant comprising: a) reacting a compound of formula (I) with a compound of formula (II) to obtain a compound of formula (III) wherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph ​​and tert-butoxyl, and X is: i) Cl when R is 4-fluorophenyl or -OCH2Ph, or ii) -OC (=O) -O-tert-butyl when R is tert-butoxyl; b) reacting the compound of formula (III) with trifluoromethanesulfonic acid anhydride, adding 3-methyl-1,2,4-thiadiazol-5-carbohydrazide and heating the resulting mixture to a temperature of at least 40 °C in the presence of an alcohol solvent to obtain a compound of formula (IV) wherein R is selected from the group consisting of 4-fluorobenzoyl, -C(=O)-OCH2Ph ​​and H; when R is 4-fluorobenzoyl in the compound of formula (IV) obtained in step b), the procedure is continued with step e),omitting steps c) and d), c) when R is -C(=O)-OCH2Ph ​​in the compound of formula (IV) obtained in step b), c1) reacting said compound of formula (IV) with a source of hydrogen to obtain a compound of formula (IV) in which R is H and c2) reacting said compound of formula (IV) in which R is H with 4-fluorobenzoyl chloride to obtain a compound of formula (IV) in which R is 4-fluorobenzoyl; d) when R is H in the compound of formula (IV) obtained in step b) or in step c), reacting said compound of formula (IV) with 4-fluorobenzoyl chloride to obtain a compound of formula (IV) in which R is 4-fluorobenzoyl; e) reacting the compound of formula (IV) in which R is 4-fluorobenzoyl obtained in steps b),c) or d) with trifluoromethanesulfonic acid to obtain the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) and f) treating the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) with a basic medium to obtain fezolinetant of formula (IVa).

2. Process for preparing fezolinetant according to claim 1, wherein R is 4-fluorophenyl, X is Cl and R is 4-fluorobenzoyl.

3. Process for preparing fezolinetant according to claim 1, wherein R is -OCH2Ph, X is Cl and R is -C(=O)-OCH2Ph.

4. A process for preparing fezolinetant according to claim 1, wherein R is tert-butoxyl, X is -OC(=O)-O-tert-butyl, and R is H.

5. A process for preparing fezolinetant according to any of the preceding claims, wherein step a) is carried out in the presence of a base.

6. A process for preparing fezolinetant according to claim 5, wherein the base is selected from the group consisting of N-methylmorpholine,triethylamine and a mixture thereof.

7. A process for preparing fezolinetant according to any of the preceding claims, wherein step a) is carried out in the presence of a polar aprotic organic solvent.

8. A process for preparing fezolinetant according to claim 7, wherein the polar aprotic organic solvent is dichloromethane.

9. A process for preparing fezolinetant according to any of the preceding claims, wherein step a) is carried out at a temperature of -5 to 25 °C.

10. A process for preparing fezolinetant according to any one of the preceding claims, wherein the reaction of the compound of formula (III) with trifluoromethanesulfonic acid anhydride of step b) is carried out in the presence of a base.

11. A process for preparing fezolinetant according to claim 10, wherein the base is selected from the group consisting of triethylamine,diisopropylethylamine and a mixture thereof.

12. A process for preparing fezolinetant according to any one of the preceding claims, wherein the reaction of the compound of formula (III) with trifluoromethanesulfonic acid anhydride of step b) is carried out in the presence of a polar aprotic organic solvent.

13. A process for preparing fezolinetant according to claim 12, wherein the polar aprotic organic solvent is dichloromethane.

14. A process for preparing fezolinetant according to any one of the preceding claims, wherein the reaction of the compound of formula (III) with trifluoromethanesulfonic acid anhydride of step b) is carried out at a temperature of -25 to -10 °C.

15. A process for preparing fezolinetant according to any one of the preceding claims,wherein the heating of step b) is at a temperature of 60 to 110 °C.

16. A process for preparing fezolinetant according to any one of the preceding claims, wherein the alcohol solvent of step b) is selected from the group consisting of isopropanol, n-propanol, ethanol, and mixtures thereof.

17. A process for preparing fezolinetant according to any one of the preceding claims, wherein step e) is carried out at a temperature of 60 to 110 °C.

18. A process for preparing fezolinetant according to any one of the preceding claims, wherein step e) is carried out in the presence of an alcohol solvent.

19. A process for preparing fezolinetant according to claim 18, wherein the alcohol solvent of step e) is selected from the group consisting of isopropanol, n-propanol,ethanol and mixtures thereof.

20. A process for preparing fezolinetant according to any one of the preceding claims, wherein the basic medium of step f) is a basic aqueous solution.

21. A process for preparing fezolinetant according to claim 20, wherein the basic aqueous solution is selected from the group consisting of aqueous sodium bicarbonate solution, aqueous potassium bicarbonate solution, aqueous sodium carbonate solution, aqueous potassium carbonate solution, and mixtures thereof.

22. A process for preparing fezolinetant according to any one of claims 1, 3, and 5-21, wherein the hydrogen source of step c) is H2.

23. A process for preparing fezolinetant according to any one of claims 1 and 3-22, wherein step d) and / or step c2) is carried out in the presence of a base.

24. A process for preparing fezolinetant according to claim 23,wherein the base is N-methylmorpholine.

25. Process for preparing fezolinetant according to any one of claims 1 and 3-24, wherein step d) and / or step c2) is carried out in the presence of a polar aprotic organic solvent.

26. Process for preparing fezolinetant according to claim 25, wherein the aprotic organic solvent is dichloromethane.

27. Trifluoromethanesulfonic acid salt of fezolinetant of formula (V).

28. Trifluoromethanesulfonic acid salt of fezolinetant according to claim 27 in solid form.

29. Trifluoromethanesulfonic acid salt of fezolinetant according to claim 27 or 28, characterized in that it has a powder X-ray diffractogram measured with CuK radiation comprising peaks at 8, 1°2, 8, 7°2, 11, 0°2, 13, 6°2, 17, 3°2, 18, 9°2, 19, 7°2, 22, 4°2 all of them with a margin of error of ±0.2.

30. A trifluoromethanesulfonic acid salt of fezolinetant according to any of claims 27 to 29, characterized in that it has a powder X-ray diffractogram measured with CuK radiation essentially as shown in Figure 1.

31. A trifluoromethanesulfonic acid salt of fezolinetant according to any of claims 27 to 30, characterized in that it has a differential scanning calorimetry (DSC) pattern comprising an exothermic peak having a threshold temperature of approximately 236.8 °C ± 2 °C.

32. A compound of formula (VI) wherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph, and tert-butoxyl.

33. A compound of formula (VI) according to claim 32, wherein R is 4-fluorophenyl.

34. Use of the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) according to any one of claims 27 to 31 or of the compound of formula (VI), wherein R is selected from the group consisting of 4-fluorophenyl,-OCH2Ph ​​and tert-butoxyl, according to claim 32 or 33, in a process for preparing fezolinetant of formula (IVa),

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